Heterocyclic derivatives

ABSTRACT

The present invention relates to methods for the treatment of epilepsy and irritable bowel syndrome.

[0001] The present invention relates to a novel salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)1,2,3,4-tetrahydro-2-quinolinecarboxylic acid or a solvate thereof, to processes for its preparation,to pharmaceutical compositions containing it and to its use in therapyand in particularly its use as medicine for antagonising the effects ofexcitatory amino acids upon the NMDA receptor complex.

[0002] The compound7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid of formula (I) is inter alia described in WO 99/64411 which alsorefers to physiologically acceptable salts thereof and more particularlyit describes an enantiomer of the compound of formula (I), which isreferred to therein as enantiomer A and a sodium salt thereof.

[0003] The enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid is a particularly potent antagonist of the NMDA receptor complex,and for its use in medicine there exists a need for the compound to beprepared in a form suitable for ease of isolation in a large scalemanufacture and for ease of formulating into an acceptable product foradministration to patients. These requirements are not conveniently metby either enantiomer A or sodium salt thereof.

[0004] It has been found that the meglumine salt of enantiomer A canreadily be prepared and isolated suitable in a pure form by a processthat is suitable for use on a large scale, and the said salt can beconveniently obtained with the required high degree of purity and goodstability and thus fulfils the exacting criteria required in thepreparation of pharmaceutical compositions for administration topatients.

[0005] The present invention thus provides the meglumine salt ofenantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid of formula (I) or a solvate (e.g. hydrate) thereof (hereinafterreferred to as the compound of the invention).

[0006] Particularly the invention provides the meglumine salt ofenantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid in a crystalline form.

[0007] More particularly, according to one embodiment, the inventionprovides for a hydrate crystalline form of the the meglumine salt ofenantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid (hereinafter referred to as form 1), characterised by the followingX-ray powder diffraction pattern expressed as 2 Theta (θ) value Angle 2θ 4.356 18.641 22.993 11.263 18.725 23.681 11.659 20.546 25.043 12.75721.362 25.598 12.877 22.234 26.823 13.962 22.379 28.753 15.482 22.80117.242 22.921

[0008] According to a further embodiment of the invention there isprovided for another crystalline form of the meglumine salt ofenantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid (hereinafter referred to as form 2) characterised by the followingX-ray powder diffraction pattern expressed as 2 Theta (θ) value Angle 2θ 5.480 19.553 25.225 8.233 20.505 25.802 10.942 21.939 26.484 15.29922.787 27.524 16.424 23.154 27.865 16.658 23.381 28.547 19.116 24.19438.345

[0009] The compound of the invention can be obtained in more than onecrystalline form. It is to be understood that the invention includes allsuch forms or mixture thereof.

[0010] The compound of the invention is an excitatory amino acidantagonist. More particularly it is a potent antagonist at thestrychnine insensitive glycine binding site associated with the NMDAreceptor complex. As such it is a potent antagonist of the NMDA receptorcomplex. This compound is therefore useful in the treatment orprevention of neurotoxic damage or neurodegenerative diseases. Thus thecompound is useful for the treatment of neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospam, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia cardiac arrest. The compound of the invention isuseful in the treatment of chronic neurodegenerative diseases such as:Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateralsclerosis, Glutaric Acidaemia type, multi-infarct dementia, statusepilecticus, contusive injuries (e.g. spinal cord injury and headinjury), viral infection induced neurodegeration (e.g. AIDS,encephalopaties), Down syndrome, ocular neurodegeneration (e.gglaucoma), epilepsy, schizophrenia, depression, migraine, headachesincluding cluster headaches and or tension headaches, anxiety, pain (e.ginflammatory pain and neuropathic pain), neurogenic bladder, irritablebowel syndrome and or visceral hyperalgesia, emesis, irritative bladderdisturbances, drug dependency, including withdrawal symptoms fromalcohol, cocaine, opiates, nicotine (e.g. smoking cessation)benzodiazepines and. inhibition of tolerance induced by opioids (i.e.morphine).

[0011] The potent and selective action of the compound of the inventionat the strychnine-insensitive glycine binding site present on the NMDAreceptor complex may be readily determined using conventional testprocedures. Thus the ability to bind at the strychnine insensitiveglycine binding site was determined using the procedure of Kishimoto Het al., J Neurochem 1981, 37, 1015-1024. The selectivity of the actionof compounds of the invention for the strychnine insensitive glycinesite was confirmed in studies at other ionotropic known excitatory aminoacid receptors. Thus the compound of the invention was found to showlittle or no affinity for the kainic acid (kainate) receptor,a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptoror at the NMDA binding site.

[0012] The compound of the invention may be found to inhibit NMDAinduced convulsions in mice using the procedure Chiamulera C et al.,Psychopharmacology (1990), 102, 551-552.

[0013] The neuroprotective activity of the compound of the invention maybe demonstrated in the middle cerebral artery occlusion preparation inmice, using the procedure described by Chiamulera C. et al., EuropeanJournal of Pharmacology, 216 (1992) pp. 335-336.

[0014] The ability of compound of the invention to alleviate withdrawalsymptoms from nicotine following smoking cessation may be demonstratedin conventional tests of nicotine induced relapse using the proceduredescribed in C. Chiamulera et al., Arch. Pharmacol., 358, 1998.

[0015] The ability of the compound of the invention to inhibit pain maybe demonstrated in conventional analgesic screen such as those describedby Dubuisson and Dennis, Pain, 1977, 4:161-174; J. J. Bennett and J. KXue, Pain, 1988, 41, 87-107.

[0016] The invention also provides for the use of the compound of theinvention for use in therapy and in particular use as medicine forantagonising the effects of excitatory amino acids upon the NMDAreceptor complex.

[0017] The invention also provides for the use of the compound of theinvention for the manufacture of a medicament for antagonising theeffects of excitatory amino acids upon the NMDA receptor complex.

[0018] According to a further aspect, the invention also provides for amethod for antagonising the effects of excitatory amino acids upon theNMDA receptor complex, comprising administering to a patient in needthereof an antagonistic amount of the compound of the invention.

[0019] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylactics as well as the treatment ofestablished diseases or symptoms.

[0020] It will further be appreciated that the amount of the compound ofthe invention required for use in treatment will vary with the nature ofthe condition being treated, the route of administration and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician. In general however doses employed for adulthuman treatment will typically be in the range of 2 to 800 mg per day,dependent upon the route of administration.

[0021] Thus for parenteral administration a daily dose will typically bein the range 20-100 mg, preferably 60-80 mg per day. For oraladministration a daily dose will typically be within the range 200-800mg, e.g. 400-600 mg per day.

[0022] The desired dose may conveniently be presented in a single doseor as divided doses administered at appropriate intervals, for exampleas two, three, four or more sub-doses per day.

[0023] While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

[0024] The invention thus further provides a pharmaceutical formulationcomprising the compound of the invention together with one or morepharmaceutically acceptable carriers thereof and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be‘acceptable’ in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

[0025] The compositions of the invention include those in a formespecially formulated for oral, buccal, parenteral, inhalation orinsufflation, implant or rectal administration.

[0026] Tablets and capsules for oral administration may containconventional excipients such as binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone; fillers, for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol;lubricants, for example, magnesium stearate, stearic acid, talc,polyethylene glycol or silica; disintegrants, for example, potato starchor sodium starch glycollate, or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art. Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup, gelatin,hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gelor hydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan mono-oleate or acacia; non-aqueous vehicles (which may includeedible oils), for example, almond oil, fractionated coconut oil, oilyesters, propylene glycol or ethyl alcohol; solubilizers such assurfactants for example polysorbates or other agents such ascyclodextrins; and preservatives, for example, methyl or propylp-hydroxybenzoates or ascorbic acid. The compositions may also beformulated as suppositories, e.g. containing conventional suppositorybases such as cocoa butter or other glycerides.

[0027] For buccal administration the composition may take the form oftablets or lozenges formulated in conventional manner.

[0028] The composition according to the invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

[0029] For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs, with the use of a suitablepropellant, such as dichlorodifluoromethane, tirchlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitablepropellants, such as dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, orfrom a nebuliser. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.

[0030] Alternatively, for administration by inhalation or insufflation,the compounds according to the invention may take the form of a drypowder composition, for example a powder mix of the compound and asuitable carrier such as lactose or starch. The powder composition maybe presented in unit dosage form in, for example, capsules or cartridgesof e.g. gelatin, or blister packs from which the powder may beadministered with the. aid of an inhaler or insufflator.

[0031] The composition according to the invention may also be formulatedas a depot preparation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus for example, thecompounds of the invention may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

[0032] The compositions according to the invention may contain between0.1-99% of the active ingredient, conveniently from 30-95% for tabletsand capsules and 3-50% for liquid preparations.

[0033] A further aspect of the invention provides a process for thepreparation of the compound of the invention.

[0034] Thus in one embodiment compound of the invention may be preparedby treating a solution of the enantiomer A (I) with megiumine in asuitable solvent such as aprotic solvent (i.e. actetone,tetrahydrofuran) or alkanol such as ethanol.

[0035] The invention further provides a method for producing thecompound of the invention in a crystalline form.

[0036] Thus the compound of the invention in hydrate crystalline form(form 1) may be prepared by treating a solution of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)1,2,3,4-tetrahydro-2-quinolinecarboxylicacid in ethanol with meglumine dissolved in water.

[0037] The reaction is carried out at room temperature and in anenvironment free of the compound of the invention in crystalline form 2.

[0038] The crystalline form 2 may obtained by crystallisation of thecompound of the invention from a mixture of water and a water miscibleorganic antisolvent.

[0039] Suitable water miscible organic antisolvents for use in thecrystallisation include alkanol (e.g. ethanol, IMS (ethanol/methanol95/5) or isopropanol), acetone or acetonitrile.

[0040] A particularly convenient water miscible organic antisolvent isethanol or acetone.

[0041] Conveniently the crystallisation process is carried out by addingthe antisolvent to a solution of the compound of the invention dissolvedin water.

[0042] In a further embodiment of the process, the crystalline form 2may be obtained by crystallisation of the compound of the invention froma mixture of suitable organic solvents.

[0043] Thus, form 2 may be obtained by dissolution of the compound ofthe invention in a suitable organic solvent (i.e. N,N-dimethylformamideor 1-methyl-2-pyrrolidone) followed by treatment with a suitable organicantisolvent such as alkanol (e.g. ethanol, IMS (ethanol/methanol 95/5)or isopropanol) or an aprotic solvent (e.g. acetone, tetrahydrofurandichloromethane, ethylacetate, toluene, or acetonitrile).

[0044] The process is preferably carried out at a temperature rangingbetween 20-45° C.

[0045] The enantiomer A of the compound of formula (I) may be preparedaccording to the processes described in WO 99/64411 which isincorporated by reference.

[0046] In a preferred embodiment, the enantiomer A of the compound offormula (I) may be prepared by stereoselective enzymatic hydrolysis ofcompounds of formula (II) with ferulic acid esterase in a pure form.

[0047] wherein R is a carboxyl protecting group.

[0048] Suitable carboxyl protecting group R for use in this reactionincludes C₁₋₄ alkyl such as methyl, ethyl, propyl, butyl or arylmethylgroups such as benzyl, nitrobenzyl or trityl.

[0049] The reaction is conveniently carried out in an aprotic solventsuch as DMSO, tetrahydrofuran in the presence of a suitable aqueousbuffer (i.e. citrate, phosphate buffer or CaCl2). If required, asolubilising agent such as Tween-80 may be added to the reactionmixture.

[0050] In a further process the enzyme may be immobilized and thereaction is carried out in essentially “neat” water-saturated organicsolvents such as methyl tert-butyl ether or tert-amyl alcohol.

[0051] The stereoselective enzymatic hydrolysis of compounds of formula(II) with ferulic acid esterase in a pure form is novel and represents afurther aspect of the invention.

[0052] The invention also extends to the meglumine salt of enantiomer Aof7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid of formula (I) or a solvate thereof when prepared from theenantiomer A of formula (I) which has been obtained by stereoselectiveenzymatic hydrolysis of compounds of formula (II) with ferulic acidesterase in a pure form.

[0053] Meglumine is commercially available (Aldrich).

[0054] In the Intermediates and Example unless otherwise stated: Meltingpoints (m.p.) were determined on a Gallenkamp m.p. apparatus and areuncorrected. All temperatures refer to ° C. Proton Magnetic Resonance(¹H-NMR) spectra were recorded at 500 MHz, chemical shifts are reportedin ppm downfield (d) from Me₄Si, used as internal standard, and areassigned as singlets (s), doublets (d), doublets of doublets (dd),triplets (t), quartets (q) or multiplets (m). Column chromathography wascarried out over silica gel (Merck AG Darmstaadt, Germany).DBU=1,8-diazobicyclo [5,4,0]undec-7-ene.

[0055] The X-ray powder diffraction pattern of a crystalline form of thecompound of the invention was obtained by loading the sample into thediffractometer (Siemens D5005 X-ray diffractometer equipped with θ/θgoniometer, scintillation counter and graphite monochromator. Thediffractometer was set up with the instrumental parameters given below:

[0056] Instrumental parameters

[0057] MONOCHROMATIC RADIATION: Cu-1.54056/1.54439

[0058] 2θ RANGE: 2°-40° 2θ

[0059] GENERATOR VOLTAGE/CURRENT: 40 kV/50 mA

[0060] STEP SIZE: 0.02° 2θ

[0061] TIME PER STEP: 2 sec⁻¹

[0062] ROTATION: on

[0063] DIVERGENCE/ANTISCATTERING SLIT: variable

[0064] SAMPLE HOLDER: round cavity on low-background plate.

[0065] The spectrum obtained was analysed using the data evaluationsoftware EVA3.0.

[0066] Enantiomer A refers to a single enantiomer whose absolute stereochemistry was not determined

[0067] Intermediate 1

[0068] (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-pentenoate

[0069] To a solution of 2-iodo 4 chloro aniline (9.1 g) in dry toluene(150 ml) ethyl glyoxylate (50% solution in toluene, 14.6 ml) and MgSO₄(2 g) were added and the resulting suspension was refluxed overnight. Itwas then filtered and concentrated to dryness under high vacuum at 50°C. for 1.5 h. The resulting brown oil was dissolved in dichloromethane(150 ml) cooled to −78° C. and TiCl₄ (99.995% purity, 4 ml) was addedvia syringe. The suspension was stirred 15 min at −78° C., then allowedto warm to rt over 15 min before being cooled again to −78° C.Allyltributyltin (17 ml) was then added and the reaction allowed toproceed for 1 h. The black solution was poured into 200 ml of ethylacetate and washed first with a saturated solution of NH₄Cl (2×150 ml),then with water and brine. The organic phase was dried and concentratedto give the crude product, which was purified by column chromatography(cyclohexane, then cyclohexane/ethyl acetate 98/2) to give the titlecompound (10.4 g) as a colourless oil.

[0070] NMR (CDCl₃) δ (ppm) 7.57 (d, 1H), 6.49 (dd,1H), 6.45 (dd,1H),5.79 (m, 1H), 5.25 (dd, 1H) 5.24 (dd, 1H), 4.83 (d, 1H), 4.25 (q,2H),4.13 (m, 1H), 2.66 (m, 2H), 1.30 (t, 3H)

[0071] Intermediate 2

[0072] (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-oxobutanoate

[0073] A solution of intermediate 1 (5.2 g) in dichloromethane (150 ml)was cooled to −78° C. and ozone was bubbled through it until the clearsolution became brick-red. At this point the flux of ozone wasinterrupted and the solution was purged with nitrogen for a few minutes.Triphenyl phosphine (7.1 g) was added and stirring continued for 1.5 h,without control of the temperature. The resulting solution was pouredinto 200 ml of ethyl acetate and washed first with a saturated solutionof NH₄Cl (2×150 ml), then with water and brine. The organic phase wasdried and concentrated to give the crude product, which was purified bycolumn chromatography (cyclohexane/ethyl acetate 80/20) to give thetitle compound (2.4 g) as a colourless oil.

[0074]¹NMR (DMSO) δ (ppm) 9.80 (t,1H), 7.57 (d,1H), 6.55 (d,1H), 6.51(dd, 1H), 4.99 (d,1H), 4.46 (m,1H), 4.24 (q, 2H), 3.08 (m, 2H), 1.28 (t,3H)

[0075] Intermediate 3

[0076] (±) E-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-Pyrrolidinylidene)butanoate (4a);(±)-Z-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate(4b)

[0077] To a solution of intermediate 2 (2.4 g) in acetonitrile (100 ml)at r.t. intermediate 3(3.7 g) and DBU (13 ml) were added and stirringwas continued overnight at −20° C. The crude solution was poured into200 ml of ethyl acetate and washed with a saturated solution of NH₄Cl(2×150 ml), then with water and brine. The organic phase was dried andconcentrated to give the crude product as a 4/1 mixture of 4a/4bcompounds. Purification by column chromatography (cyclohexane/ethylacetate 80/20) gave the title 4a (2.16 g) and the 4b (0.5 g) compoundsas colourless oils.

[0078] Intermediate 3a

[0079]¹NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.56 (d, 1H), 7.38 (t, 2H),7.16 (t, 1H), 6.6 (m, 1H), 6.50 (dd, 1H), 6.49 (d, 1H), 4.88 (d, 1H),4.26 (m, 3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H)

[0080] Intermediate 3b

[0081]¹NMR (CDCl₃) δ (ppm) 7.69 (d, 2H), 7.52 (d, 1H), 7.38 (t, 2H),7.17 (t, 1H), 6.47 (d, 1H), 6.44 (dd, 1H), 5.98 (m, 1H), 5.00 (d, 1H),4.22 (m, 2H), 4.13 (m, 1H), 3.84 (t, 2H), 3.2-3.6 (m, 2H), 2.85 (m, 2H),1.26 (t, 3H)

[0082] Intermediate 4

[0083] (±)-Ethyl7-chloro-4-2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic

[0084] To a solution of intermediate 3b (370 g) in toluene (5.2 lit),Triethylamine (248 ml), Triphenylphosphine (7.4 g) and PdCl₂ (2.52 g)were added. The resulting solution was warmed to 100° C. and stirred for2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) wasadded.

[0085] The reaction mixture was washed with NH₄Cl 8% (3×5.2 lit) andwater (5.2 lit). The organic layer was filtered over a celite pad and itwas washed with toluene (1 lit); then it was distilled under vacuum(T=50° C.; P=60 mbar) to reach 6.3 lit. After cooling to T=20-25° C.,isooctane (5.2 lit) was dropped over 30 min. The precipitate was stirredfor 2 h 30 min then it was filtered and washed with a mixturetoluene/isooctane 1/1 (1.85 lit). The yellow solid was dried in vacuumat T=40° C. for 18 h to obtain the title compound as a yellow solid (210g).

[0086] m.p. 160-162° C.

[0087]¹NMR (DMSO): 7.72 (m, 2H); 7.39 (m, 2H); 7.20 (d, 2H); 7.15 (m,2H); 6.96 (dd, 1H); 6.74 (d, 1H); 6.57 (dd, 1H); 4.29 (dd, 1H); 4.21 (m,1H); 4.02 (m, 1H); 3.93 (m, 1H); 3.82 (m, 1H); 3.69 (m, 1H); 3.20 (m,1H). 2.92 (m, 2H); 2.92 (m, 2H); 0.93 (t, 3H).

EXAMPLE 1

[0088] (−)Meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid (form 2)

[0089] Method A

[0090] 16.5 g of Lipase Amano AP12 (Aspergillus niger lipase) weresuspended in 360 ml of 0.1 M citrate buffer (pH=3) in a stirred vesselat 15° C.

[0091] 27.5 g of intermediate 4 were dissolved in 190 ml of dimethylsulphoxide at 20° C. and this solution added into the vessel undervigorous stirring.

[0092] The mixture was stirred at 37° C. for 24 hrs and 27.5 g of filteraid (Dicalite) were added to the reaction mixture which was then cooledto 20° C. After addition of 275 ml of aq. 0.2 M hydrochloric acid themixture was cooled to +6° C. and then filtered.

[0093] The filter cake was washed with 140 ml of aq. 0.2 M hydrochloricacid and 140 ml of water before being dried.

[0094] The so obtained dried filter cake (55 g) was extracted at 20° C.with 660 ml of acetone, then filtered off washing with 220 ml ofacetone. To the filtrate, 33 ml of an aqueous solution of meglumine (0.2g/ml) were added. The so obtained suspension was digested and the solidfiltered and washed with 275 ml of acetone. After drying the crude titlecompound was obtained as a yellow solid (16.2 g).

[0095] 4 g of this crude compound were then dissolved in 10 ml of waterby heating at 50° C., then 110 ml of EtOH were added. After digestion at20° C. the solid was filtered and dried to obtain the purified titlecompound as a yellow solid (3.75 g), m.p. 186 C.°.

[0096] The title compound (5 mg) was dissolved in 1 ml of a mixtureD₂O/DMSO 95/5.

[0097]¹H-NMR (D₂O/DMSO 95/5) δ (ppm) 7.44 (2H, d), 7.37 (2H, t), 7.19(1H, t), 7.16 (1H, d), 6.66 (1H, d), 6.58 (1H, dd), 3.96 (1H, m),3.78-3.50 (8H, m), 3.46 (1H, dd), 3.99 (1H, dd), 3.10 (1H, dd), 3.05(1H, d), 3.02 (2H, m), 2.64 (3H, s).

[0098] [α]_(D=)−321.7; λ=598 nm; 20° C. conc mg/ml 0.12%solvent=methanol.

[0099] Method B

[0100] To a warmed at 35° C. 0.1 M Sodium citrate buffer obtained bymixing a 0.1 M aqueous solution (412 ml) of citric acid and a 0.1 Maqueous solution (196 ml) of trisodic citrate dihydrate into a jacketedreactor, an aqueous solution (Conc=40 mg/ml) of the enzyme ferulic acidesterase (19.6 ml) and dimethyl sulfoxide (98 ml) were added. To theresulting solution, a solution of Intermediate 4 (49 g) in dimethylsulfoxide (270 ml) was added. Then the mixture was stirred at 37-38° C.for 24 hrs.

[0101] After cooling at 20° C. the reaction mixture was extracted twicewith 2-butanone (1470 mL) and the organic layer was washed with a 6%sodium chloride aqueous solution (2×980 ml) and a 25% sodium chlorideaqueous solution (392 ml) then, after addition of further 2-butanone(490 ml) the solvent was distilled off at atmospheric pressure to aresidual 200 ml volume. Then acetone (1323 ml) was added to the mixtureand a 20% aqueous meglumine solution (60 ml) was dropped into themixture. The resulting suspension was stirred for 1 h, then filtered,washed with acetone (490 ml) and dried at 40° C. under vacuum for ca 16hrs to obtain the crude title compound as a yellow solid (26.9 g).

[0102] 26.8 g of the crude title compound was dissolved with water(107,2 ml) at 55° C. and after filtration cooled at 45° C. Then acetone(268 ml) was dropped under stirring and the mixture seeded with thetitle compound. Acetone (402 ml) was then further added and theresulting slurry was stirred at 20° C. for 1 hr and at 2° C. for 2 hrsand then solid was filtered washed with acetone (134 ml) and dried undervacuum at 40° C. for ca 1 6 hrs to obtain the title compound (23 g),m.p. 185-187° C. TABLE 1 The X-ray powder diffraction pattern of theproduct of Example 1 in terms of ‘d’ spacings is as follows Angle (°2θ)d value (A) 5.480 16.114 8.233 10.731 10.942 8.079 15.299 5.787 16.4245.393 16.658 5.317 19.116 4.639 19.553 4.536 20.505 4.328 21.939 4.04822.787 3.899 23.154 3.838 23.381 3.801 24.194 3.676 25.225 3.528 25.8023.450 26.484 3.363 27.524 3.238 27.865 3.199 28.547 3.124 38.345 2.346

Example 2

[0103] (−)Meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid (form 1)

[0104] (−)-Sodium7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic2.5g) was suspended in ethyl acetate (75 ml) and extracted with aqueous HCl1.5N (25 ml). The organic layer was evaporated to dryness to obtain7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)1,2,3,4-tetrahydro-2-quinoline-2-carboxylic acid_as a white foam (2.3 g) which was dissolved inethanol (69 ml) at 23° C. under nitrogen and then a solution ofmeglumine (1.25 g) in water (5.3) was added in 20 minutes. Thesuspension was stirred at 23° C. under nitrogen for 24 hours. The solidwas filtered and dried at 40° C. for 20 hours (3.0 g), m.p. 112° C.

[0105]¹H-NMR (D₂O/DMSO 95/5) δ (ppm) 7.73 (2H, d), 7.38 (2H, t), 7.15(1H, d), 7.13 (1H, t), 6.77 (1H, d), 6.45 (1H, dd), 6.40 (1H, bs), 4.10(1H, bm), 3.79 (3H, m), 3.64 (1H, dd), 3.60 (1H, bm), 3.55 (1H, dd),3.47 (1H, m), 3.40 (1H, d). 3.38 (1H, t), 3.16 (1H, m), 2.98 (1H, m),2.85 (1H, m), 2.78 (1H, m), 2.70 (1H, bm), 2.42 (3H, s).

[0106] X ray powder diffraction data are reported in Table 2. TABLE 2The X-ray powder diffraction pattern of the product of Example 2 interms of ‘d’ spacings is as follows Angle (°2θ) d value (A) 4.356 20.27011.263 7.849 11.659 7.584 12.757 6.934 12.877 6.869 13.962 6.337 15.4825.719 17.242 5.139 18.641 4.756 18.725 4.735 20.546 4.319 21.362 4.15622.234 3.995 22.379 3.969 22.801 3.897 22.921 3.877 22.993 3.865 23.6813.754 25.043 3.553 25.598 3.477 26.823 3.321 28.753 3.102

Pharmacy Examples

[0107] A. Capsules/ Tablets Active ingredient 20.0 mg Starch 1500 32.5mg Microcrystalline Cellulose 200.0 mg Croscarmellose Sodium 6.0 mgMagnesium Stearate 1.5 mg

[0108] The active ingredient is blended with the other excipients. Theblend can be used to fill gelatin capsules or compressed to form tabletsusing appropriate punches. The tablets can be coated using conventionaltechniques and coatings.

[0109] B. Tablets Active ingredient 20.0 mg Sorbitol 200.0 mgMicrocrystalline Cellulose 70.0 mg Povidone 25.0 mg CroscarmelloseSodium 6.0 mg Magnesium Stearate 1.5 mg

[0110] The active ingredient is blended with lactose, microcrystallinecellulose and part of the croscarmellose sodium. The blend is granulatedwith povidone after dispersing in a suitable solvent (i.e. water). Thegranule, after drying and comminution is blended with the remainingexcipients. The blend can be compressed using appropriate punches andthe tablets coated using conventional techniques and coatings.

[0111] C. Bolus Active ingredient 0.1-32 mg/ml Trometamol 1.0-5.0 mg/mlwater for injection qs to 1 ml

[0112] The formulation may be packed in glass ampoules or vials andsyringes with a rubber stopper and a plastic/metal overseal (vialsonly).

[0113] D. Infusion Active ingredient 0.01-3.2 mg/ml Trometamol 0.2-1.0mg/ml 5% dextrose injection qs to 100 ml

[0114] The formulation may be packed in glass vials or plastic bags.

[0115] No untoward effects have been observed when compound of theinvention has been administred to mice at the pharmacological activedoses.

1. The meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid.
 2. A crystalline form of the compound as claimed in claim
 1. 3.The crystalline form described in Example
 1. 4. A process for thepreparation of the compound claimed in any of the claims 1 to 3 whichcomprises mixing enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid with meglumine in a suitable solvent.
 5. A process for thepreparation of a crystalline form as claimed in claim 2 or 3 whichcomprises crystallising the meglumine salt from a mixture of water and awater miscible organic solvent or from a mixture of suitable organicsolvents.
 6. A pharmaceutical composition comprising a compound asclaimed in any of claims 1 to 3 in admixture with one or morephysiologically acceptable carriers or excipients.
 7. Use of a compoundas claimed in any claims from 1 to 3 as medicine for antagonising theeffects of excitatory amino acids upon the NMDA receptor complex.
 8. Amethod of treatment of a mammal including man for conditions whereantagonising the effects of excitatory amino acids on the NMDA receptorcomplex is of therapeutic benefit, comprising administration of aneffective amount of a compound as claimed in any of claims 1 to 3.